Liver cancer-also called hepatocellular carcinoma (HCC)-is the most frequent primary liver cancer... more Liver cancer-also called hepatocellular carcinoma (HCC)-is the most frequent primary liver cancer in humans. As of today, it is mainly induced by chronic virus infections such as Hepatitis B and C viruses, which induce chronic hepatitis and fibrosis, the two most important conditions predisposing towards HCC development. Besides, chronic alcohol or drug consumption contributes to chronic liver injury and HCC development. Of note, in industrialized countries virus infections have recently been outcompeted by a high-fat and high-sugar diet as the most important etiology for HCC development in humans-now representing the fastest growing cancer in the USA as of today. It is believed that soon also in Europe high-fat diet caused HCC will become the fastest growing cancer. Today more than 800,000 people die every year due to cancer; however, despite a great research effort in the last 20 years, no efficient curative therapy is available at the moment. It has turned out that various subtyp...
Aims Previous thorax irradiation promotes metastatic spread of tumor cells to the lung. We hypoth... more Aims Previous thorax irradiation promotes metastatic spread of tumor cells to the lung. We hypothesized that vascular damage facilitates lung metastasis after thorax irradiation and that therapeutically applied multipotent mesenchymal stromal cells (MSCs) with reported repair activity may prevent these adverse effects of ionizing radiation by protecting lung endothelia from radiation-induced damage. Results Previous whole thorax irradiation (WTI) with 15Gy significantly enhanced seeding and metastatic growth of tumor cells in the lung. WTI was further associated with endothelial cell damage, senescence of lung epithelial cells and up-regulation of invasion- and inflammation-promoting soluble factors, e.g. endothelial matrix metalloproteinase 2 (Mmp2), its activator Mmp14, the co-factor tissue inhibitor of metalloproteinases 2 (Timp2), chemokine (C-C motif) ligand 2 (Ccl2), and urokinase-type plasminogen activator (Plau/uPA), and recruitment of CD11b+CD11c- myelomonocytic cells. Inhibition of Mmp2 counteracted radiation-induced vascular dysfunction without preventing increased metastasis. In contrast, therapy with bone marrow or aorta-derived MSCs within two weeks post-irradiation antagonized radiation-induced damage to resident cells as well as the resulting secretome-changes and abrogated the metastasis-promoting effects of WTI. Innovation Therapy with MSCs protects lungs from radiation-induced injury and reduces the risk of lung metastasis. MSC-mediated inhibition of Mmp2 mediates their protective effects at the vasculature. Further local and systemic effects such as inhibition of radiation-induced senescence of bronchial epithelial cells and associated secretion of immunomodulatory factors may participate in the inhibitory effect of MSCs on lung metastasis. Conclusion MSC-therapy is a promising strategy to prevent radiation-induced lung injury and the resulting increased risk of metastasis.
Liver cancer-also called hepatocellular carcinoma (HCC)-is the most frequent primary liver cancer... more Liver cancer-also called hepatocellular carcinoma (HCC)-is the most frequent primary liver cancer in humans. As of today, it is mainly induced by chronic virus infections such as Hepatitis B and C viruses, which induce chronic hepatitis and fibrosis, the two most important conditions predisposing towards HCC development. Besides, chronic alcohol or drug consumption contributes to chronic liver injury and HCC development. Of note, in industrialized countries virus infections have recently been outcompeted by a high-fat and high-sugar diet as the most important etiology for HCC development in humans-now representing the fastest growing cancer in the USA as of today. It is believed that soon also in Europe high-fat diet caused HCC will become the fastest growing cancer. Today more than 800,000 people die every year due to cancer; however, despite a great research effort in the last 20 years, no efficient curative therapy is available at the moment. It has turned out that various subtyp...
Aims Previous thorax irradiation promotes metastatic spread of tumor cells to the lung. We hypoth... more Aims Previous thorax irradiation promotes metastatic spread of tumor cells to the lung. We hypothesized that vascular damage facilitates lung metastasis after thorax irradiation and that therapeutically applied multipotent mesenchymal stromal cells (MSCs) with reported repair activity may prevent these adverse effects of ionizing radiation by protecting lung endothelia from radiation-induced damage. Results Previous whole thorax irradiation (WTI) with 15Gy significantly enhanced seeding and metastatic growth of tumor cells in the lung. WTI was further associated with endothelial cell damage, senescence of lung epithelial cells and up-regulation of invasion- and inflammation-promoting soluble factors, e.g. endothelial matrix metalloproteinase 2 (Mmp2), its activator Mmp14, the co-factor tissue inhibitor of metalloproteinases 2 (Timp2), chemokine (C-C motif) ligand 2 (Ccl2), and urokinase-type plasminogen activator (Plau/uPA), and recruitment of CD11b+CD11c- myelomonocytic cells. Inhibition of Mmp2 counteracted radiation-induced vascular dysfunction without preventing increased metastasis. In contrast, therapy with bone marrow or aorta-derived MSCs within two weeks post-irradiation antagonized radiation-induced damage to resident cells as well as the resulting secretome-changes and abrogated the metastasis-promoting effects of WTI. Innovation Therapy with MSCs protects lungs from radiation-induced injury and reduces the risk of lung metastasis. MSC-mediated inhibition of Mmp2 mediates their protective effects at the vasculature. Further local and systemic effects such as inhibition of radiation-induced senescence of bronchial epithelial cells and associated secretion of immunomodulatory factors may participate in the inhibitory effect of MSCs on lung metastasis. Conclusion MSC-therapy is a promising strategy to prevent radiation-induced lung injury and the resulting increased risk of metastasis.
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